When a patient presents with a hyperpigmented macule, one of the first conditions that comes to mind is neurofibromatosis. However, a variety of normal and pathologic conditions are associated with hyperpigmented macules. Here we present a selection of such lesions and their associated conditions. The collection is by no means comprehensive. For example, patients with Silver-Russell syndrome or Bloom syndrome may have multiple café au lait macules, but photographs of such patients are not included.
We hope this Photo Essay will serve as a reminder that hyperpigmented macules may appear in a wide variety of conditions—both benign and pathologic.
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Becker Nevus
This 13-year-old boy has a Becker nevus--also called Becker melanosis, because the lesions do not contain nevus cells. This common lesion is characterized by the abrupt onset of hyperpigmentation that gradually expands; it appears at or before adolescence. The male-to-female ratio is approximately 5:1.Becker nevi are usually unilateral and are commonly located on the shoulder or upper chest.
Half of Becker nevi are associated with hypertrichosis. The hairs usually become coarser and darker with time.A variety of bone and tissue abnormalities have been reported in patients with Becker nevi (eg, arm hypoplasia, pectus excavatum, absent pectoralis major muscle), albeit in a minority of those affected.
Becker nevus is not a true nevus. The risk of melanoma developing within the lesion is the same as that for uninvolved skin.
Solitary and Multiple Café au Lait Macules
The 12-year-old boy in Figure A has one large and one small café au lait macule and a single hypopigmented macule. Solitary café au lait macules may be present in as many as 30% of newborns. They vary in size from a few millimeters to several centimeters. The macules may be inconspicuous until the affected area is exposed to the sun.
Parents frequently ask about these lesions. Fortunately, the vast majority of solitary café au lait macules have no clinical significance. This patient enjoys robust good health.
In contrast, the 9-year-old girl in Figure B shows classic features of neurofibromatosis type 1 (NF-1) with axillary freckling and multiple café au lait macules.
NF-1 may be diagnosed when any 2 of the following are present:
1. Six or more café au lait macules over 5 mm in diameter in prepubertal persons or over 15 mm in postpubertal persons.
2. Axillary or inguinal freckling.
3. Two or more iris Lisch nodules.
4. Two or more neurofibromas or one plexiform neurofibroma.
5. A distinctive osseous lesion.
6. Optic gliomas.
7. A first-degree relative with NF-1.
Café au lait macules are present in 100% of patients with NF-1; these are usually scattered over the trunk and extremities. Their size, number, and pigmentation increase with age.
Neurofibromas--like the one shown in Figure C in a 19-year-old woman--are small, rubbery lesions with a purplish discoloration overlying the skin. They may also be situated along peripheral nerves and blood vessels within viscera. Plexiform neurofibromas may appear as larger, more hyperpigmented café au lait macules. These lesions result from thickening of nerve trunks and are usually located in the orbital or temporal region.
Fanconi Anemia
This is an autosomal recessive syndrome characterized by chromosomal breakage, pancytopenia, and various congenital abnormalities. It is a heterogeneous condition clinically and has been linked to defects in at least 8 different genes. Fifty percent to 65% of affected persons demonstrate areas of hyper- or hypopigmentation. Café au lait macules, like those shown in Figure A in a 9-year-old boy, are seen in approximately 25% of those affected.
Skeletal abnormalities are another hallmark of Fanconi anemia: hypoplasia of the thumbs and radii are the most common findings. Figure B demonstrates hypoplasia of the thenar eminence in the same 9-year-old boy. Other skeletal abnormalities include hip dislocation, scoliosis, and vertebral anomalies. Low birth weight and subsequent short stature, microphthalmia, microcephaly, developmental delay, renal and genital anomalies, GI defects, and cardiac defects also have an increased association with this condition. However, 1 out of 3 affected persons demonstrates no obvious congenital deformities.
Urticaria Pigmentosa
This 4-year-old boy has urticaria pigmentosa--one of a group of disorders in which mast cells group together in the skin. Patients may have solitary mastocytomas or (rarely) diffuse infiltration of the skin with mast cells.
The lesions shown here are typical of urticaria pigmentosa. They are hyperpigmented macules that are mostly uniform in size and are distributed mainly on the trunk. They differ from lentigines, nevus cell nevi, and café au lait spots in one striking way. When one of the lesions of urticaria pigmentosa is rubbed or stroked, the mast cells contained therein release their contents (histamine, prostaglandins, leukotrienes, etc), with a resultant local hive or blister. This phenomenon--the Darier sign--is not demonstrated by nevi or café au lait macules.
Other varieties of mastocytosis may be associated with systemic symptoms related to the release of a large amount of mediators from a large number of mast cells (eg, episodic flushing, palpitations, or syncope). Patients may also have extracutaneous aggregates of mast cells in the bone, lungs, kidneys, or intestinal wall.
McCune-Albright Syndrome
McCune-Albright syndrome is classically described as a triad of polyostotic fibrous dysplasia, café au lait macules, and precocious puberty. The syndrome may also be accompanied by various other endocrinopathies including hyperthyroidism, acromegaly, hyperprolactinemia, Cushing syndrome, and hypophosphatemic rickets. Some patients may also exhibit hepatic, cardiac, and GI dysfunction.
The syndrome is more common in girls than boys, but both sexes are affected. It is caused by a mutation in the alpha subunit of a G protein. This mutation results in increased signal transduction along the cAMP pathway, which stimulates growth and function of the gonads, adrenal cortex, specific pituitary cell populations, osteoblasts, and melanocytes.
The hyperpigmented lesions in McCune-Albright syndrome are classically described as "coast of Maine" macules with broad, irregular borders. The 14-year-old patient pictured here demonstrates a characteristic macule. These lesions are typically larger than macules in other conditions and are often found over the sacrum, buttocks, and upper spine. As a rule, fewer than 6 lesions are present. About half of the time, they are unilateral and follow the lines of Blaschko (see case on page 322). If the lesions are unilateral, they are usually found on the same side on which the skeletal abnormalities are more prominent. *
Segmental Café au Lait Macule
This 11-year-old boy has a segmental café au lait macule in a zosteriform distribution. Because the presence of such a lesion may signify somatic mosaicism, a careful review of systems and physical examination of affected patients is indicated. The same cautions apply to patients with large (10-cm) café au lait macules. This patient is vigorously healthy.
Lines of Blaschko
There are several disorders of hyperpigmentation that follow the lines of Blaschko--and this distribution can aid in their diagnosis. The lines of Blaschko were originally described by Alfred Blaschko in 1901. He recognized the pattern as distinct from dermatomes and Langer lines. The lines of Blaschko form a "V" shape over the spine, "S" shapes over the lateral and anterior aspects of the trunk, and a linear pattern over the extremities. It is thought that these lines represent normal embryonic movements of the skin during embryogenesis. The manifestation of certain diseases along these lines is believed to represent somatic mosaicism, with abnormal skin surrounded by normal skin clearly showing the distinction. Several of the diseases of hyperpigmentation we present here follow these lines--as evidenced in the following photos.
Pigmentary mosaicism. The patient in Figure A, a 6-month-old girl, demonstrates the phenomenon of pigmentary mosaicism. The areas of hyperpigmentation follow the lines of Blaschko. The phenomenon of pigmentary mosaicism was first described by Ito in 1952. Since that time, there has been an expanding recognition of a group of disorders that affect both sexes in which chromosomal mosaicism is always suspected and frequently demonstrated--albeit sometimes with great difficulty. Case reports and series describe patients with a wide variety of other abnormalities that may involve the hair, teeth, eyes, heart, and CNS. Often patients have no other abnormalities. Disorders of pigmentary mosaicism differ from incontinentia pigmenti in that both sexes are affected, and the pigmentary changes with mosaicism--which may be hyper- or hypopigmentation--are not preceded by vesicular or verrucous lesions as they are in incontinentia pigmenti.
Proteus syndrome. This rare disorder is characterized by overgrowth of multiple tissues in a mosaic pattern. The term "proteus" is derived from the Greek sea god of the same name, who had the ability to appear in the form of any creature to avoid being captured. The same is true of this heterogeneous disorder that can involve the skin, subcutaneous tissue, connective tissue, CNS, and the viscera. The most common clinical manifestations are epidermal pigmented nevi, nevi on the palms and soles, hyperostosis, local gigantism, hemihyperplasia, and multiple lipomas in the subcutaneous tissues and abdominal and pelvic cavities. The nevi typically follow the lines of Blaschko.
Figure B shows an epidermal nevus in the axilla of a 4-year-old girl with this disorder. Figure C demonstrates gigantism of this girl's fingers.
